Crosslinked polymers and refractive devices formed therefrom

ABSTRACT

A polymer is formed of ethylenically unsaturated monomers including a zwitterionic monomer, an aromatic monomer and a cross-linking monomer. Preferably the crosslinking monomer includes at least one a group containing compound and at least one aliphatic group containing compound. The polymer is water-swellable and a hydrogen has optical and mechanical properties rendering it suitable for use as an intraocular refractive device such as an intraocular lens.

BACKGROUND OF THE INVENTION

The present invention relates to a polymeric composition, which is acrosslinked water swellable polymer, the hydrogel of which istransparent and has a high refractive index, rendering it useful for usein a refractive device, for instance an intraocular lens.

RELEVANT PRIOR ART

Various products have been developed for replacing or augmenting thenatural lens. Replacement lenses may be used where the original lens isclouded by cataracts. Lenses which augment the natural lens and whichare intended to be inserted into the eye, include intraocular contactlenses, corneal implants, corneal inlays and corneal onlays.

A method of implanting an intraocular lens in a rolled up form, tominimise the size of the incision is in widespread use. Such a device isdescribed in U.S. Pat. Nos. 4,573,998 and 4,702,244. In thesespecifications, the material of the lens is described as having a shapememory. The device thus recovers its original conformation after beingreleased from the restraining insertion device through which it isintroduced. The above specifications do not describe in any detail thematerials used to form the lens.

In U.S. Pat. No. 4,608,049, a foldable intraocular lens is formed of asilicone rubber or a crosslinkedhydroxyethylmethacrylate:N-vinyl-2-pyrrolidone:methacrylic acid polymer,that is a water-swellable material.

Further descriptions of hydrogel intraocular lenses are by Barrett inU.S. Pat. No. 4,664,666. Barrett uses a hydrogel ofhydroxyethylmethacrylate, a common component of hydrogel contact lenscompositions. One problem with poly HEMA hydrogels is that therefractive index of the gel is relatively low. It is preferred for ahydrogel to have higher refractive indices, for instance at least 1.45,up to around 1.60.

Higher refractive index materials are described in EP-A0485197. Thepolymers must be formed of at least two aryl acrylate polymers, forinstance 2-phenylethyl acrylate and 2-phenylethyl methacrylate. Thecrosslinker is selected from aliphatic diacrylates. The refractiveindices of the material is in the range 1.553 to 1.556. The polymers arenot, however, hydrogels (that is they are not water-swellable).

EP-A-0308130 describes elastic intraocular lenses formed of copolymersof methacrylate and acrylate esters which are respectively relativelyhard and relatively soft at body temperature. The monomers are allaliphatic acrylates. The crosslinker is an aliphatic dimethacrylate.

In our earlier application WO-A-9207885, we describe crosslinkedpolymers formed of zwitterionic monomer and nonionic copolymerisablemonomer, and hydrogel lenses formed therefrom. The examples all used analkyl acrylate or hydroxyalkylacrylate comonomer. The crosslinkingmonomers were all aliphatic di-ethylenically unsaturated compounds.

In EP-A-0563299 a copolymer of a zwitterionic monomer and a nonionicmonomer is used as a contact lens. In the worked examples, comonomersare hydroxyethylmethacrylate, N-vinylpyrollidone and methylmethacrylate.Crosslinkers are all aliphatic compounds (allyl methacrylate anddiethylene glycol di-methacrylate).

In U.S. Pat. Nos. 5,391,669 and 5,270,415, hydrogels formed of balancedcharge ion pairs and nonionic comonomer are used as contact lenses. Thebalanced charge ion pair may be a zwitterionic monomer. In the workedexamples, the nonionic comonomers are selected from hydroxyethylmethacrylate, silyl group containing monomers, alkyl methacrylates,hydroxypropyl methacrylate, fluoroalkyl methacrylate and hydroxypropylmethacrylamide. Crosslinkers used in the worked examples are allaliphatic compounds.

SUMMARY OF THE INVENTION

A new crosslinked polymer according to the invention is obtainable byradical polymerisation of ethylenically unsaturated monomers including

a) a zwitterionic monomer of the general formula I

YBX  I

wherein

B is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylenechain optionally containing one or more fluorine atoms up to andincluding perfluorinated chains or, if X or Y contains a terminal carbonatom bonded to B, a valence bond;

X is a zwitterionic group; and

Y is an ethylenically unsaturated polymerisable group selected from

CH₂═C(R)—CH₂—O—, CH₂═C(R)—CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)—O—,CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)—O—, RCH═CHC(O)O—,RCH═C(COOR²)CH₂—C(O)—O—,

wherein:

R is hydrogen or a C₁-C₄ alkyl group;

R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are asdefined above; and

R² is hydrogen or a C₁₋₄alkyl group or BX where B and X are as definedabove;

A is —O— or —NR¹—;

K is a group —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—,—(CH₂)_(p)NR³—, —(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—,—(CH₂)_(p)NR³C(O)O—, —(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (inwhich the groups R³ are the same or different), —(CH₂)_(p)O—,—(CH₂)_(p)SO₃—, or, optionally in combination with B, a valence bond andp is from 1 to 12 and R³ is hydrogen or a C₁-C₄ ₄ group.

b) an aromatic group containing monomer of the general formula II

Y¹R⁴  II

wherein Y¹ is selected from

CH₂═C(R⁵)—CH₂—O—, CH₂═C(R⁵)—CH₂OC(O)—, CH₂═C(R⁵)OC(O)—, CH₂═C(R⁵)—O—,CH₂═C(R⁵)CH₂OC(O)N(R⁶)—, R⁷OOCCR⁵═CR⁵C(O)—O—, R⁵CH═CHC(O)O—,R⁵CH═C(COOR⁷)CH₂—C(O)—O—,

wherein:

R⁵ is hydrogen or a C₁-C₄ alkyl group,

R⁶ is hydrogen or a C₁-C₄ alkyl group or R⁵ is R³;

R⁷ is hydrogen or a C₁₋₄ alkyl group or R³;

A¹ is —O— or —NR⁵—; and

K¹ is a group —(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, —(CH₂)_(q)OC(O)O—,—(CH₂)_(q)NR⁸—, —(CH₂)_(q)NR⁸C(O)—, —(CH₂)_(q)C(O)NR⁸—,—(CH₂)_(q)NR⁸C(O)O—, —(CH₂)_(q)OC(O)NR⁸—, —(CH₂)_(q)NR⁸C(O)NR⁸— (inwhich the groups R⁸ are the same or different), —CH₂)_(q)O—,—(CH₂)_(q)SO₃—, or a valence bond and p is from 1 to 12 and R⁸ ishydrogen or a C₁-C₄ alkyl group;

and R⁴ is an aromatic group; and

c) a cross-linking monomer of the general formula III

(Y²)_(n)R⁹  III

in which n is an integer of at least 2, each Y² is selected from

CH₂═C(R¹⁰)—CH₂—O—, CH₂═C(R¹⁰)—CH₂OC(O)—, CH₂═C(R¹⁰)OC(O)—,CH₂═C(R¹⁰)—O—, CH₂═C(R¹⁰)CH₂OC(O)N(R¹¹)—, R¹²OOCCR¹⁰═CR¹⁰C(O)—O—,R¹⁰CH═CHC(O)O—, R¹⁰CH═C(COOR¹²)CH₂—C(O)—O—,

wherein:

R¹⁰ is hydrogen or a C₁-C₄ alkyl group;

R¹¹ is hydrogen or a C₁-C₄ alkyl group or R¹¹ is R³;

R¹² is hydrogen or a C₁₋₄ alkyl group or R³;

A² is —O— or —NR¹¹—;

K² is a group —(CH₂)_(r)OC(O)—, —(CH₂)_(r)C(O)O—, —(CH₂)_(r)OC(O)O—,—(CH₂)_(r)NR¹²—, —(CH₂)_(r)NR¹³C(O)—, —(CH₂)_(r)C(O)NR¹³—,—(CH₂)_(r)NR¹³C(O)O—, —(CH₂)_(r)OC(O)NR¹³—, —(CH₂)_(r)NR¹³C(O)NR¹³— (inwhich the groups R¹³ are the same or different), —(CH₂)_(r)O—,—(CH₂)_(r)SO₃— or a valence bond and r is from 1 to 12 and R¹³ ishydrogen or a C₁-C₄ alkyl group;

and R⁹ is an n-functional organic group.

Suitable examples of aromatic groups R⁴ are optionally substitutedaralkyl and alkaryl groups. Most preferably, a group R⁴ is anunsubstituted aryl or aralkyl group, in which the alkyl group has 1 to 4carbon atoms, for instance benzyl, 2-phenylethyl or phenyl.

For optimum copolymerisability, the groups Y, Y¹ and Y² have the samegeneral definition. Most preferably each such group is an (alk)acrylicor a styrenic group. An acrylic group, H₂C═C(H or Me)CO—(O or NH) areparticularly preferred. Preferably all such groups are eithermethacrylic R=R⁵=R¹⁰=Me) or acrylic (R, R⁵, R¹⁰=hydrogen), and arepreferably all ester or amide derivatives thereof. Most conveniently,the monomers are all acrylic esters, generally either methacrylateesters or acrylate esters.

In the invention, it is found that optimum crosslinking of the aromaticand zwitterionic monomers is achieved where a crosslinking monomer ofthe formula III in which the group R⁹ is an aromatic group is included.Suitable aromatic groups are, for instance, phenylene, alkarylene,aralkylene, and bisphenol A-type groups. Most preferably the crosslinkerincludes bisphenol A dimethacrylate. The crosslinker may be di-, tri-,tetra- or higher functional, for instance an oligomeric or polymericcompound.

It is found to be particularly preferred for the crosslinking monomer toinclude a monomer of the general formula III in which the group R⁹ is analiphatic group. Suitable aliphatic groups R⁹ are C₂₋₈-alkylene,C₂₋₄-alkyleneoxy-C₂₋₄-alkylene or oligo(C₂₋₄-alkyleneoxy)-C₂₋₄-alkylene(e.g. —(CH₂CH₂O)_(t)CH₂CH₂—, where t is 1-50).

Most preferably a mixture of crosslinking agents is included, includingat least one crosslinking agent in which R⁹ is an aromatic group and atleast one crosslinking agent in which R⁹ is an aliphatic group.

In the general formula I, the zwitterionic group preferably has thegeneral formula IV

in which the moieties X⁴ and X⁵, which are the same or different, are—O—, —S—, —NH— or a valence bond, preferably —O—, and W⁺ is a groupcomprising an ammonium, phosphonium or sulphonium cationic group and agroup linking the anionic and cationic moieties which is preferably aC₂₋₁₂ alkylene group,

preferably in which W⁺ is a group of formula —W¹—N⁺R¹⁴ ₃, —W¹—P⁺R¹⁵ ₃,W¹—S⁺R¹⁵ ₂ or —W¹-Het⁺ in which:

W¹ is alkylene of 1 or more, preferably 2-6 carbon atoms optionallycontaining one or more ethylenically unsaturated double or triple bonds,disubstituted-aryl, alkylene aryl, aryl alkylene, or alkylene arylalkylene, disubstituted cycloalkyl, alkylene cycloalkyl, cycloalkylalkylene or alkylene cycloalkyl alkylene, which group W¹ optionallycontains one or more fluorine substituents and/or one or more functionalgroups; and

either the groups R¹⁴ are the same or different and each is hydrogen oralkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenylor two of the groups R¹⁴ together with the nitrogen atom to which theyare attached form a heterocyclic ring containing from 5 to 7 atoms orthe three groups R¹⁴ together with the nitrogen atom to which they areattached form a fused ring structure containing from 5 to 7 atoms ineach ring, and optionally one or more of the groups R¹⁴ is substitutedby a hydrophilic functional group, and

the groups R¹⁵ are the same or different and each is R¹⁴ or a groupOR¹⁴, where R¹⁴ is as defined above; or

Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferablynitrogen-, containing ring, for example pyridine.

Most preferably, the zwitterionic group of the formula IV, has thegeneral formula V:

where the groups R¹⁶ are the same or different and each is hydrogen orC₁₋₄ alkyl, and m is from 1 to 4, in which preferably the groups R¹⁶ arethe same.

Alternatively, the zwitterionic group may be a betaine group (ie inwhich the cation is closer to the backbone), for instance a sulpho-,carboxy- or phospho-betaine. A betaine group should have no overallcharge and is preferably therefore a carboxy- or sulpho-betaine. If itis a phosphobetaine the phosphate terminal group must be a diester,i.e., be esterified with an alcohol. Such groups may be represented bythe general formula VI

—X²—R¹⁷—N^(⊕)(R¹⁸)₂—R¹⁹—V^(⊖)  VI

in which X² is a valence bond, —O—, —S— or —NH—, preferably —O—;

V is a carboxylate, sulphonate or phosphate diester(monovalentlycharged) anion;

R¹⁷ is a valence bond (together with X²) or alkylene —C(O)alkylene- or—C(O)NHalkylene preferably alkylene and preferably containing from 1 to6 carbon atoms in the alkylene chain;

the groups R¹⁸ are the same or different and each is hydrogen or alkylof 1 to 4 carbon atoms or the groups R¹⁸ together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 atoms; and

R¹⁹ is alkylene of 1 to 20, preferably 1 to 10, more preferably 1 to 6carbon atoms.

One preferred sulphobetaine monomer has the formula VII

where the groups R²⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl and s is from 2 to 4.

Preferably the groups R²⁰ are the same. It is also preferable that atleast one of the groups R²⁰ is methyl, and more preferable that thegroups R²⁰ are both methyl.

Preferably s is 2 or 3, more preferably 3.

Alternatively the zwitterionic group may be an amino acid moiety inwhich the alpha carbon atom (to which an amine group and the carboxylicacid group are attached) is joined through a linker group to thebackbone of polymer A. Such groups may be represented by the generalformula VIII

in which X³ is a valence bond, —O—, —S— or —NH—, preferably —O—,

R²¹ is a valence bond (optionally together with X³) or alkylene,—C(O)alkylene- or —C(O)NHalkylene, preferably alkylene and preferablycontaining from 1 to 6 carbon atoms; and

the groups R²² are the same or different and each is hydrogen or alkylof 1 to 4 carbon atoms, preferably methyl, or two of the groups R¹⁹,together with the nitrogen to which they are attached, form aheterocyclic ring of from 5 to 7 atoms, or the three group R²² togetherwith the nitrogen atom to which they are attached form a fused ringstructure containing from 5 to 7 atoms in each ring.

The mole ratio of zwitterionic monomer to aromatic group containingmonomer is generally in the range 1:99 to 99:1, preferably 1:20 to 1:1,more preferably in the range 1:10 to 1:2. The amount of zwitterionicmonomer in total monomer is preferably in the range 1 to 95%, morepreferably 5 to 50%, most preferably 10 to 25%. The amount of aromaticgroup containing monomer is preferably in the range 10 to 99%, morepreferably 50 to 95%, most preferably 75 to 90%.

In the polymerisation mixture, the crosslinking monomer is generallypresent in a molar amount in the range 0.01% to 10%, most preferably inthe range 0.1 to 5% based on total moles of monomer. Where a mixture ofaromatic group containing cross-linking monomer to aliphatic groupcontaining monomer is used the molar ratio of the two is preferably inthe range 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 2:1 to1:2 most preferably 3:2 to 2:3.

The zwitterionic group containing monomer is generally included insufficient levels to render the polymer swellable in water and to renderthe hydrogel more biocompatible.

According to a further aspect of the invention, there is provided ahydrogel formed of the novel crosslinked polymer and, dispersedthroughout the polymer, an aqueous liquid. The water content of thepolymer when fully swollen in deionised water is preferably in the range10 to 50%, for instance in the range 20 to 40%, most preferably in therange 25 to 35%.

Preferably the hydrogel (the polymer swollen in water) is transparent.It is found that the hydrogel of the invention has a high transmissionrate for visible light. The average transmission rate should preferablybe above 90% throughout the range of visible light, 400 to 700 nmwavelengths.

The incorporation of the aromatic monomer enables high refractiveindices to be achieved. Thus the refractive index of the fully waterswollen hydrogel, may be at least 1.45, for instance up to 1.60.Preferably the refractive index is in the range 1.45 to 1.55.

The present invention includes also a polymerisation process, in whichthe mixture of monomers a, b and c are subjected to conditions wherebypolymerisation is initiated and propagated. Initiation may be by anysuitable means, for instance using thermal, redox or UV initiators,optionally in combination with one another. The polymer of theinvention, when used as an intraocular lens, may include an absorber ofultraviolet light.

Since the zwitterionic monomer tends to be very polar and aromaticmonomers tend to be non polar, the monomers may be immiscible with oneanother. In order to achieve a homogenous polymerisation mixturetherefore it may be necessary to include a non polymerisable diluentliquid which acts as a common solvent for the monomers. A suitablesolvent is an alcohol. The solvent is generally removed from the productpolymer after polymerisation, for instance by evaporation or by solventreplacement using an alternative liquid, generally water or otheraqueous solution.

It is generally necessary to include any non polymerisable liquiddiluent in an amount in the range 5 to 90% by weight based on the totalweight of the polymerisation mixture. In order to avoid unnecessarysolvent removal, the level is preferably less than 75%, for instanceless than 50%. It is generally necessary to include at least 10% toachieve adequate dissolution of the monomers.

The polymerisation is generally conducted in some form of mould, forinstance to form precursor products from which shaped lenses may beformed. Where such products are for instance rods, buttons or other lensprecursors, shaping to form appropriate three dimensional shapes isgenerally by lathing. In order for lathing to take place, it isgenerally necessary to remove any polymerization diluent prior tocarrying out the lathing step.

Alternatively the lens or other final product may be polymerised in amould of the desired final shape. In this case, the solvent is removedafter polymerisation, for instance by solvent replacement.

For any polymerisation method, a final step in the formation of ahydrogel product involves swelling the crosslinked polymer in an aqueousliquid. The materials, when swollen in water have very desirablemechanical properties, for instance enabling them to be used as foldableIOL's. The strain at break for the swollen materials may be at least50%, or even more than 100%. The modulus should preferably be in therange 1 to 4 MPa.

The materials (xerogels) have hardness values high enough to render themsuitable for shaping by machining, for instance, by lathe cutting.

The product is found to have very desirable mechanical, optical andbiocompatible properties rendering it suitable for use as a refractivedevice. The polymers are of particular value for use as intraoculardevices especially intraocular lenses (IOL's) such as replacementlenses, lenses to augment the natural lens, e.g. posteria chamber phakicIOL's, anterior chamber phakic IOL's, corneal implants such as cornealinlays, corneal onlays and intracorneal rings.

The improved biocompatibility resulting from the incorporation of azwitterionic monomer is believed to result in less damage being causedby a phakic lens on the natural lens (avoiding cataract formation) or onthe iris by chafing. For any intraocular device the improvedbiocompatibility should result in reduced inflammatory response. Theresults presented hereinafter show that the materials cause lessendothelial damage than prior art materials.

The following examples illustrate the invention.

Abbreviations

EWC=Equilibrium Water Contact

RI=Refractive Index

Trans=Optical transmission

BA=Benzyl acrylate

HEMA-PC=2-Methacryloyloxyethyl-2′-trimethylammonium ethyl phosphateinner salt

LM=Lauryl Methacrylate

EGDMA=Ethylene glycol dimethacrylate

BADMA=Bisphenol-A dimethacrylate

FEM=Fluoroethyl Methacrylate

AIBN=Azoisobutyronitrile

General Polymerisation Method

The monomers, including the crosslinking monomer, in the desiredquantities, were dissolved in dry ethanol, in an amount of 20% (based ontotal polymerization mixture weight) unless otherwise specified.Initiator of the desired type and in the desired amount was dissolvedinto the mixture (AIBN, unless otherwise specified). The liquidpolymerization mixture was thoroughly degassed using nitrogen. Thepolymerisation mixture was then injected into the desired mould (to forma membrane or button, as the case may be) which bad previously beenflushed with nitrogen. The mould was subsequently sealed and suspendedin a water bath (containing oxygen scavenger) at the desired temperature(usually 60° C.) for the desired period (usually sixteen hours) tocomplete polymerisation. Unless otherwise specified, the polymer, stillin the mould after removal from the water bath, was annealed undervacuum at 90° C. for a further sixteen hours, before being removed fromthe moulds. For all button polymerisations, the buttons, after removalfrom the mould, were annealed at 110° C. under vacuum for 4 days.

Mechanical Properties

EWC

The EWC is measured by weighing hydrogel lenses in their fully hydratedstate and after drying in an oven overnight at 110° C.

Refractive Index

The retractive index is measured on an Atago device with the material infully swollen (in water) form.

Hardness

The hardness of the F-type button (from which a lens is cut) is measuredusing a Type D Shore Durometer. A cross section is cut from the buttonusing a microslicer or lathe and the centre and edge hardness recorded.This test is carried out on the xerogel.

Expansion Factor

This is determined from the ratio of diameter of lens hydrated todiameter of lens dry.

Tensile Properties

The mechanical analysis is carried out as a tensile test using a MiniInstron 44, using a 5 load cell at a speed of 5 mm per minute. Thematerial is tested at 25+/−2° C. and kept hydrated throughout the test.

Biological Properties

The following tests are carried out on disks cut from polymer membranes,unless otherwise specified.

Fibrinogen Adhesion

This assay quantifies protein deposited on a test surface usingpolycolonal anti serum and enzyme-conjugated secondary anti serum. Itprovides a useful assessment of haemocompatibility and generalbiocompatibility.

Buttons of test material are each placed into a well of a twenty fourwell plate.

One microgram fibrinogen in 50 μl PBS. The fibrinogen solution is leftin contact with the samples for two hours at room temperature.Subsequently the samples are washed three times with PBS, excess bindingsites are blocked by overnight incubation with 4% bovine serum albuminin PBS at 4° C. The buttons are subsequently washed three times with PBSand replaced into fresh wells of a new 24 well plate. 500 μl dilutedantithuman fibrinogen antiserum (1:5000 in PBS) is added and incubatedwith the samples for 30 minutes at room temperature. The buttons arewashed three times in PBS and placed into fresh wells of a 24 wellplate. 500 μl diluted horseradish peroxidase-conjugated rabbit anti-goatantiserum (1:500 in PBS) is added and incubated for 30 minutes at roomtemperature. The buttons are washed three times in PBS and placed intofresh wells of a further 24 well plate. A substrate for the peroxidaseenzyme is subsequently added in an appropriate buffer after contact withthe samples for 10 minutes at room temperature. A terminator is addedand the solutions read in a suitable colour remitter. The results arereported in terms of relative light units as compared to PMMA and pHEMAcontrols. High values thus correspond to high levels of adhesion.

Bacterial Adhesion Assay

This assay measures the bacterial (Staphylococcus epidermidis)attachment on the test materials using extraction of cellular ATP ofattached bacterial cells. Extracted ATP is evaluated usingbioluminescent technique. If bacteria adhere to and are carried with anintraocular lens into the eye, they could cause an infection.

Samples of the material under test are placed in the desired number ofwells in a microtitre plate. A bacterial suspension at 3×10⁸ CFU per mlin phosphate buffered saline is incubated in the wells for four hours at37° C. under agitation. The bacterial suspension is aspirated from thewells and samples subsequently rinsed in sterile phosphate bufferedsaline before being placed into the wells of a new plate. Lysis buffer(0.1% trichloroacetic acid, 1% xylenol 2 mM EDTA in deionised water) isplaced into the well and left in contact with the sample for 10 minutesto extract the ATP. Extracted ATP is diluted with tris acetate buffer1:1, ATP monitoring reagent is added and light emission determined in abioluminescent plate reader. Bioluminessence is related to a number ofbacterial cells by generating a calibration curve.

Fibroblast Adhesion Assay

This assay determines the adhesion of a standard adherent cell line,mouse 3T3 fibreblasts, in tissue culture medium, to samples on the test.

The fibroblast cells are cultivated in a tissue culture step toconfluent or near confluent monolayer. The monolayer is detached fromthe flask using a solution of trypsin-EDTA, and subsequently suspendedin serum-containing medium. Test disks of the material under test of 13mm diameter are placed into twenty four well plates. 0.5 mls of cellsuspension (having a cell concentration of 3000 per ml) is added andincubated for 72 hours at 37° C. The samples are removed from the wellsand washed with PBS. The samples with adherent cells are placed intowells of a new plate and subjected to lysis for 30 minutes at roomtemperature followed by freezing overnight. After addition of furtherlysis buffer, ATP monitoring reagent is added to the wells andluminescence subsequently read to determine ATP levels. The results arereported in terms of relative light units as compared to standardmaterials (polymethylmethacrylate and polyhydroxyethylmethacrylate).

Granulocyte Activation

This method measures granulocyte activation in response to superoxideradicals by disks of materials under test. It is a useful measure ofbiocompatibility. The cells subjected to the test are polymorphonuclearleucocytes (PMN's) from venus blood. Incubation of the cells in thepresence of the materials under test is conducted in the presence ofnitroblue tetrazolium, which detects the oxidative burst triggered byinflammatory materials upon granulocyte activation to be visualisedcolorimetrically.

PMN's are separated from venus blood using a suitable technique. Theyare suspended in Earl's salt solution containing 10% foetal calf serumat a cell density of 1×10⁶ cells per ml. 100 μl of the cell suspensionis contacted with 13 mm disks of samples under test in the wells of amicrotitre plate. After 30 minutes at 37° C., the samples in the wellsare washed three times with phosphate buffered saline and then 100 μl ofnitroblue tetrazolium is added to the wells. Adherent cells areincubated with the NBT solution for at least one hour at 37° C.Subsequently cells are fixed using formaldehyde, washed and viewed underlight microscopy. Activated granulocytes appear blue. The number ofactivated granulocytes as compared to polymethylmethacrylate controlsand positive controls (polymethylmethacrylate treated with phorbol esteras a positive control).

Macrophage Adhesion

This protocol measures macrophage adhesion to test surfaces, anotheruseful measure of biocompatibility. The protocol involves incubationwith novel materials overnight which exploits the known tendency ofmacrophages to attach to plastics surfaces.

Suitable purification steps are conducted to separate out mononuclearcells from venus blood. The cells are suspended in serum-free macrophagemedium (commercially available) at a concentration of 10⁶ cells per ml.200 μl of medium is added to wells of a microtitre plate containing 13mm diameter disks of materials under test. The plates are left overnightat 37° C. after which disks are moved to a new plate and washed threetimes before fixing with formaldehyde and staining with Dakoanti-macrophage antibody-biotin conjugate. Attached antibody issubsequently visualised using a Sigma high intensity rapid stain kitcontaining an avidin-peroxidase conjugate with 3-amino-9-ethyl carbazole(AEC) as chromogen. The numbers of macrophages is determined using lightmicroscopy and compared against controls.

Rabbit Epithelial Lens Cell Adhesion

AGO4677, a mortal primary rabbit lens epithelial cell strain wasobtained from the National Institute of Aging (NIA) repository (Cambden,N.J., USA). The cells were cultures in Minimal Essential Eagles Medium(MEM) with double the normal concentration of non-essential amino acids(Gibco) and 10% (v/v) foetal calf serum (FCS) at a density of 6000 cellscm⁻² at 37° C. in 5% CO₂. The cells were never permitted to becomeconfluent under maintenance conditions and were passaged by routinetrypsin dispersion. Adhesion of the AGO4677 was assayed by ATPextraction 72 h after 1000 viable rabbit lens cells were plated ontodiscs of material. ATP was liberated by incubating each disk with 100 μlof a sterile hypotonic lysis buffer (0.01M Tris-Acetate pH 8, 2 mMEDTA). The ATP solution was then diluted 1:1 with a commercial assaybuffer designed for ATP luminometry (0.1 M Tris-Acetate pH 8, 2 mM EDTA)and the amount of ATP in each sample measured using a commercial kit(BioOrbit-Wallac, Turku Finland) and a 96 well plate luminometer(Amerlite, Amersham).

Corneal Endothelial Cell Touch Test

This test method is a highly discriminating assay for intraocular lensutility. The test involves contacting materials under test with aconfluent monolayer of bovine corneal endothelium (BCE) cells for apredetermined period of time and qualitatively assessing the damage tothe monolayer.

Confluent monolayers of BCE cells in sterile tissue culture dishes areestablished by culturing in the presence of dulbecco's modified eaglesmedium (DMEM) containing foetal bovine serum, new born calf serum,penicillin and streptomycin. The monolayers were rinsed to removeunattached cells. A sterile 13 mm disk of test sample (xerogel) isrinsed ten times with sterile PBS to hydrate. The hydrated disk is thenplaced on the BCE monolayer surface and a weight placed upon the top ofa disk to ensure contact (in the “Av Damage”, and HamaIP tests (seeTable 7) a 2 g weight was used, whilst a lighter weight was used for the“cell damage” results). After a predetermined period of time (3½minutes) the disk is removed, fresh medium is added and the cellsincubated for 15 minutes to allow recovery. The cells are then viewedunder inverted light microscope and the damage is qualitatively assessedon a numerical scale of 0 (complete destruction) to 10 (minimal damage).Values are given as Av(erage) Damage in results. The cells are alsoanalysed by fixing, staining with Harris hematoxylin solution and viewedusing Argus 50 software and a Hamamatsu image processor (Hama IP). Theresults of the quantitative determination are expressed in terms of meanpercent damage (sample number six).

EXAMPLE 1

Polymerisations were conducted to form membranes using the generalpolymerisation method between two glass plates lined with PET andseparated by a PTFE spacer using azoisobutyronitrile and 20 weight %ethanol. The effect of including diluent monomer, lauryl methacrylate orfluoroethylmethacrylate, was investigated in these experiments. Themonomers, and their proportions are shown in Table 1, as are the resultsof performing test methods for RI, EWC and visible light transmission at700 nm and 480 nm on polymer fully swollen in water.

TABLE 1 Mole % Properties Example BA HEMA-PC LM FEM BADMA EGDMA RI 700nm 450 nm EWC 1.1.1 83   15  0 0 1 1 1.4555 94.5  89.26 37.6 1.1.2 83  15  0 0   0.75   1.25 1.4585 94.79 89.9  37.7 1.1.3 83   15  0 0   0.5  1.5 1.451  94.87 89.58 39.6 1.1.4 79   15  0 0 1 5 1.4805 95.66 93.6929.9 1.2.1 78   15  0 5 1 1 1.4565 — — 38.2 1.2.2 73   15  0 10  1 11.452  — — 38.1 1.2.3 63   15  0 20  1 1 1.447  — — 37.3 1.2.4 53   15 0 30  1 1 1.4405 — — 38.1 1.3.1 83   15  0 0 1 1 1.462  89.15 82.5437.9 1.3.2 78   15  5 0 1 1 1.459  87.46 81.31 35.7 1.3.3 73   15 10 0 11 1.454  86.31 77.2  36.3 1.3.4 63   15 20 0 1 1 1.4505 90.18 82.99 35.01.3.5 53   15 30 0 1 1 1.446  93.31 88   31.8 1.3.6 43   15 40 0 1 11.483  94.31 88.01 29.7 1.4.1 73.5 15 10 0 1   0.5 1.454  88.2  81.3837.0 1.4.2 63.5 15 20 0 1   0.5 1.46  91.34 84.72 36.2 1.5.1 83.5 15  00   0.5 1 1.449  81.68 74.37 42.6 1.5.2 83   15  0 0 1 1 1.457  86.2881.85 38.4 1.5.3 82   15  0 0 2 1 1.4715 76.84 72.11 33.2 1.5.4 84   15 0 0 1 0 1.465  93.87 91.48 35.8 1.5.5 83.5 15  0 0 1   0.5 1.4485 89.5983.98 40.6 1.5.6 82   15  0 0 1 2 — 91.63 84.81 41.0 1.6.1 83   15  0 01 1 1.454  85.98 81.01 39.1 1.6.2 78   15  5 0 1 1 1.4535 87.31 81.4139.2 1.6.3 73   15 10 0 1 1 1.454  85.73 78.63 38.2 1.6.4 78   15  0 5 11 1.4525 85.94 79.45 39.6 1.6.5 73   15  5 5 1 1 1.4525 86.82 79.85 38.31.7.1 83   15  0 0 1 1 1.456  96.55 93.76 — 1.7.2 73   15 10 0 1 11.459  — — 33.7 1.7.3 85.5   12.5  0 0 1 1 1.469  95.82 92.58 — 1.7.475.5   12.5 10 0 1 1 — — — 30.4 1.7.5 88   10  0 0 1 1 1.488  95.8492.75 — 1.7.6 78   10 10 0 1 1 1.485  93.32 88.57 23.7

The results show that high refractive index, optically clear materialscan be formulated from monomers including HEMA-PC. These are expected tohave improved biocompatibility compared to comparative materials notcomprising pendant zwitterionic groups.

The results also show that, with the same weight proportion of HEMA-PC,replacing increasing levels of benzylmethacrylate with aliphatic diluentmonomer results in a decrease in RI, with a similar level of chargeresulting from such replacement by lauryl methacrylate or fluoroethylmethacrylate. Increasing the total level of crosslinker results in adecrease in the EWC with a corresponding increase in RI. The copolymersappear to have better transmission rates for visible light than theterpolymers. Reducing the level of HEMA-PC results in a reduction ofEWC, and an increase in RI.

EXAMPLE 2

Further polymerisations to form membranes were conducted using thegeneral method, to investigate the effect on the EWC, RI andtransmission, and also the mechanical characteristics andbiocompatibility, of changing the relative amounts of zwitterionic andaromatic group containing monomer. The biocompatibility is, in thisexperiment determined using the fibrinogen adsorption test describedabove, the control being a polymer of 98% mole benzyl methacrylate and1% each (mole) of EGDMA and BADMA crosslinker. The monomer proportionsare shown in Table 2. The results are shown in Table 3. The results showthat the strain for materials formed from monomers including laurylmethacrylate in place of benzylacrylate is reduced. The results ofexample 2.1-2.5 show that polymers having PC groups can be formed withgood mechanical and optical properties and which have goodbiocompatibility as adjudged by the reduction of fibrinogen adsorption.

TABLE 2 Mole % Monomers Example BA HEMA-PC LM 2.1 83 15 0 2.2 85.5 12.50 2.3 88 10 0 2.4 90.5 7.5 0 2.5 83 15 0 2.6 73 15 10 2.7 63 15 20 2.853 15 30 2.9 43 15 40 2.10 33 15 50

TABLE 3 Trans/ Trans. Tensile Fibr. gn. 700 nm 480 nm Modulus StrainStrength Redn. Example EWC RI % % MPa % MPa % 2.1 38.3 1.450 92.25 87.311.312 81.8 0.740 73 2.2 32   1.461 93.18 87.36 1.773 67   0.758 79 2.327.6 1.480 93.22 87.96 1.870 116.7  1.399 83 2.4 26.8 1.488 93.12 88.042.109 142.5  1.932 76 2.5 38.8 1.459 91.43 86.11 0.814 63.8 0.560 74 2.635.1 1.460 90.87 85.93 0.914 56.7 0.600 72 2.7 32.4 1.461 91.03 85.991.064 45.1 0.549 77 2.8 32.2 1.451 90.45 86.14 1.043 42.2 0.544 67 2.929.0 1.452 90.63 86.05 1.063 40.2 0.499 77  2.10 27.5 1.454 90.73 85.870.984 45.1 0.573 74

EXAMPLE 3

Polymerisations in Button Moulds

In this and the following example the effects of changing the type ofcross-linker, the level of initiator and the level of solvent on opticaland mechanical properties are investigated.

Monomers at the mole proportions shown in Table 5 were polymerised bythe general method. All polymerisation contained 15 mole % HEMA-PC andthe remaining amount after taking the cross-linker quantities intoconsideration was BA. The EF, hydrated optical clarity, EWC and hardnessof the variant buttons are shown in Table 5.

TABLE 4 AIBN Example EGDMA BADMA Level/ No. Level/mol % Level/mol % mole% Comments 3.1 0 2 0.25 — 3.2 2 0 0.25 — 3.3 2 0 0.05 — 3.4 2 0 1.0 —3.5 1.5 0.5 0.25 — 3.6 1 1 0.05 — 3.7 1 1 0.05 Repeat of 3.6 3.8 1 10.25 15 wt % ethanol 3.9 1 1 0.25 —

TABLE 5 Hy- Ex- drated am- Expansion Optical Hard- ple Appearance OtherFactor Clarity EWC ness 3.1 Buttons — x x x x turned white due to phaseseparation 3.2 Clear — 1.16 ± 0.03 clear 34.8 ± 0.1 72 ± buttons, did0.5 not shatter on annealing 3.3 Clear — 1.16 ± 0.03 clear 35.0 ± 0.0 66± buttons, 1.1 crazed effect on top surface 3.4 Buttons — x x x x turnedwhite due to phase separation 3.5 Clear — 1.15 ± 0.03 clear 32.3 ± 0.071 ± buttons 0.8 3.6 Clear — 1.13 ± 0.01 clear 30.6 ± 0.2 78 ± buttons,.08 crazed effect on top surface 3.7 Clear Repeat 1.14 ± 0.03 clear 30.5± 0.0 68 ± buttons, of 3.6 1.6 crazed effect on top surface 3.8 Clear 15wt % 1.12 ± 0.04 Slightly 29.7 ± 0.0 78 ± buttons. ethanol opaque 0.6Turn slightly opaque on hydrating 3.9.1 Clear buttons — 1.11 ± 0.02clear 29.7 ± 0.1 66 ± 0.6 3.9.2 — 1.13 ± 0.03 clear 30.7 ± 0.0 78 ± 0.53.9.3 — 1.13 ± 0.01 clear 31.5 ± 0.1 74 ± 0.5 3.9.4 — 1.13 ± 0.02 clear31.6 ± 0.1 82 ± 0.5 x - not tested

EXAMPLE 4

Slices of some of the buttons made in Example 3 were subjected tomechanical tests to give the results shown in Table 6.

TABLE 6 Variant Mechanical Properties EGDMA BADMA AIBN Modu- Sam- levellevel level lus Stress Strain ple mole % mole % mole % MPa MPa % 3.9.3 11 0.25 1.73 ± 0.89 ±  80.40 ± 0.89 0.06 17.25 3.5 1.5 0.5 0.25 0.97 ±0.61 ±  69.75 ± 0.04 0.06 5.57 3.2 2 0 0.25 0.70 ± 0.60 ± 102.98 ± 0.130.05 3.58 3.3 2 0 0.05 0.53 ± 0.51 ±  91.72 ± 0.26 0.04 14.09 3.6 1 10.05 1.16 ± 0.79 ±  77.59 ± 0.11 0.01 17.56

Discussion of Example 3 and 4

Crosslinker

The standard formulation HEMA-PC:BA:EGDMA:BADMA 15:83:1:1 was altered touse only one crosslinker, 2 mol % EGDMA or 2 mol % BADMA The productionof 2% BADMA was unsuccessful resulting in white soft buttons due tophase separation. The complete removal of EGDMA from the polymer isunfavourable, as it seems to result in a loss of clarity.

Decreasing the level of BADMA from 2 to 0 mol %, and increasing theEGDMA level to maintain 2 mol % crosslinker level overall, results inbuttons which have a higher expansion factor, higher water content andtherefore reduced mechanical properties. This trend is shown clearly inTable 5 and 6. Increasing the EGDMA level at the expense of BADMAincreases the water content due to the hydrophobic nature of BADMA.

Reducing Solvent Level

In the general method 20 wt % solvent was incorporated into theformulation to make the monomers miscible with each other. Example 3.8was carried out to examine the effect of reducing the ethanol level tojust above the lowest miscible level 15 wt %. This would reduce the timerequired to remove the solvent from the buttons before lathing. FromTable 5 it was shown that the hydrated buttons are slightly opaque.

EXAMPLE 5

Lenses were cut from some of the buttons produced in example 3.6 bylathe to a parallel mono-curve design, 0.25 mm thick. The lenses, priorto hydration, had a gem-like quality, equivalent topolymethylmethacrylate. The lenses were hydrated and subjected tomechanical testing. The hydrated lenses were tested to have a modulus of1.508±0.125 MPa, stress of 2.282±0.442 MPa and strain 102.93±15.30%.

The mechanical properties of the lenses are better than button slices ofthe same formulation. These differences may arise from the differentdimension sizes of test samples (lens 0.25 mm thick compared to slices1.50 mm thick).

EXAMPLE 6

Further membrane polymerisations were conducted using the monomermixtures shown in table 7. For all examples, the initiator level was0.25 mole % AIBN, whilst 1 mole % mole of EGDMA and BADMA were includedas crosslinkers. The aromatic group containing comonomer used was BA ineach case and that comonomer made up the remaining monomer in thepolymerisation mixture. 20 weight % ethanol (based on the totalpolymerisation mixture) was used as solvent. The level of HEMA-PC was asspecified in the table.

Discs cut from the membrane were subjected to biological evaluations.The results of the fibrinogen adsorption, fibroblast adhesion assay,bacterial adhesion assay, macrophage adhesion assay, granulocyteactivation assay and bovine corneal endothelial touch test are shown intable 7. The results show that high R1 materials (see examples 1 and 2)which are biocompatible. In combination with example 2, these resultsshow that biocompatible materials can be formulated with a range ofmechanical properties appropriate for different applications and lensdesigns.

EXAMPLE 7

In vivo experiments were conducted in which lenses of the composition ofexample 3.9 lathe cut from buttons were implanted into rabbits usingconventional equipment for insertion of IOL's in a rolled conformation.The results were successful.

The lenses were each circular and had a refractive power of about −12Din the eye. One type of lens had a diameter of 9 mm and centre thicknessof 0.6 mm, whilst the other had a diameter of 7 mm and a centrethickness of 0.2 mm.

EXAMPLE 8

The formulation of example 3.6 was prepared but with 1% (by weight) ofDaracure 1173 (CIBA GEIGY) as photoinitiator instead of AIBN, and 30% byweight of ethanol. Aliquots of the formulation were placed in circularlens molds machined from polymethylpentene (TPX Goodfellows). The moldswere sealed and subjected to ultraviolet irradiation for 1 hour (midrange UV). The cured lenses were removed and extracted with ethanol andthen water. The resulting lenses were clear and had a refractive indexof 1.48. In the BCE assay (using the lighter weight) their performancewas almost equivalent to that of the machined lenses (average score 8versus control 10 and lathed 9.5).

TABLE 7 BCE Fib'n Fibroblast Bact. Epi M'phage G'cyte Av mole % Ads'nAd'n Ad'n Ad'n Ad'n Act'n Damage HAMA Cell Example HEMA-PC Rel.Abs. RLURLU RLU RLU Av no. (2 g) IP Damage 6.1 (2.1) 15 0.0 7 0.4 3 0.1 0.7 80.02 2 6.2 (2.2) 12.5 0.2 15 2.1 4 1.6 2.9 NT 0.02 3 6.3 (2.3) 10 0.0 173.5 5 2.3 1.8 NT NT 2 6.4 (2.4) 7.5 0.5 8 5.3 6 0.2 4.7 NT NT 4 6.Slathed 15 9.5 NT NT PMMA Control — 2.0 34 11.7 47 10.6 7.5 3 1.5 9 PHEMAControl — 0.2 40 3.5 19 0.5 6.8 6 0.53 4

What is claimed is:
 1. A crosslinked polymer obtainable by radicalpolymerisation of ethylenically unsaturated monomers including a) azwitterionic monomer of the general formula I YBX  I wherein B is astraight or branched alkylene, oxaalkylene or oligo-oxaalkylene chainoptionally containing one or more fluorine atoms or, if X or Y containsa terminal carbon atom bonded to B, a valence bond; X is a zwitterionicgroup; and Y is an ethylenically unsaturated polymerisable groupselected from the group consisting of

CH₂═C(R)—CH₂—O—, CH₂═C(R)—CH₂OC(O)—, CH₂═C(R)OC(O)—, CH₂═C(R)—O—,CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)—O—, RCH═CHC(O)O—,RCH═C(COOR²)CH₂—C(O)—O—,

wherein: R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄alkyl group or R¹ is —B—X where B and X are as defined above; and R² ishydrogen or a C₁₋₄ alkyl group or BX where B and X are as defined above;A is —O— or —NR¹—; K is selected from the group consisting of—(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³—,—(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—,—(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ arethe same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and optionally incombination with B, a valence bond and p is from 1 to 12 and R³ ishydrogen or a C₁-C₄ alkyl group; b) an aromatic group containing monomerof the general formula II Y¹R⁴  II wherein Y¹ is selected from the groupconsisting of

CH₂═C(R⁵)—CH₂—O—, CH₂═C(R⁵)—CH₂OC(O)—, CH₂═C(R⁵)OC(O)—, CH₂═C(R⁵)—O—,CH₂═C(R⁵)CH₂OC(O)N(R⁶)—, R⁷OOCCR⁵═CR⁵C(O)—O—, R⁵CH═CHC(O)O—,R⁵CH═C(COOR⁷)CH₂—C(O)—O—,

wherein: R⁵ is hydrogen or a C₁-C₄ alkyl group; R⁶ is hydrogen or aC₁-C₄ alkyl group or R⁶ is R⁴; R⁷ is hydrogen or a C₁₋₄ alkyl group orR⁴; A¹ is —O— or —NR⁶—; K¹ is selected from the group consisting of—(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, —(CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR⁸—,—(CH₂)_(q)NR⁸C(O)—, —(CH₂)_(q)C(O)NR⁸—, —(CH₂)_(q)NR⁸C(O)O—,—(CH₂)_(q)OC(O)NR⁸—, —(CH₂)_(q)NR⁸C(O)NR⁸— (in which the groups R⁸ arethe same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bondand q is from 1 to 12 and R⁸ is hydrogen or a C₁-C₄ alkyl group; and R⁴is an aromatic group; and c) a cross-linking monomer of the generalformula III (Y² )_(n)R⁹  III in which n is an integer of at least 2,each Y² is selected from the group consisting of

CH₂═C(R¹⁰)—CH₂—O—, CH₂═C(R¹⁰)—CH₂OC(O)—, CH₂═C(R¹⁰)OC(O)—,CH₂═C(R¹⁰)—O—, CH₂═C(R¹⁰)CH₂OC(O)N(R¹¹)—, R¹²OOCCR¹⁰═CR¹⁰C(O)—O—,R¹⁰CH═CHC(O)O—, R¹⁰CH═C(COOR¹²)CH₂—C(O)—O—,

wherein: R¹⁰ is hydrogen or a C₁-C₄ alkyl group; R¹¹ is hydrogen or aC₁-C₄ alkyl group; R¹² is hydrogen or a C₁-C₄ alkyl group; A² is —O— or—NR¹¹—; K² is selected from the group consisting of —(CH₂)_(r)OC(O)—,—(CH₂)_(r)C(O)O—, (CH₂)_(r)OC(O)O—, —(CH₂)_(r)NR¹²—, (CH₂)_(r)NR¹²C(O)—,—(CH₂)_(r)C(O)NR¹²—, —(CH₂)_(r)NR¹²C(O)—, —(CH₂)_(r)OC(O)NR¹²—,—(CH₂)_(r)NR¹²C(O)NR¹²— (in which the groups R¹² are the same ordifferent), —(CH₂)_(r)O—, —(CH₂)_(r)SO₃— and a valence bond and r isfrom 1 to 12 and R¹² is hydrogen or a C₁-C₄ alkyl group; and R⁹ is ann-functional organic group; wherein the cross-linked polymer isswellable in water such that the water content of the polymer when fullyswollen in deionized water is in the range of 10 to 50% by weight, andthe zwitterionic monomer of general formula I is present in an amount ofat least 5 mole %, the aromatic group containing monomer of generalformula II is present in an amount of at least 10 mole %, and thecross-linking monomer of general formula III is present in an amount of0.01 to 10 mole %, based upon total monomer.
 2. A polymer according toclaim 1 in which R⁴ is benzyl or phenyl.
 3. A polymer according to claim1 in which Y and Y² are the same, and are CH₂═CR^(x)COA, in which R^(x)is methyl or hydrogen and A is
 0. 4. A polymer according to claim 1 inwhich the cross-linking monomer comprises a compound of the generalformula III in which R⁹ is an aromatic group.
 5. A polymer according toclaim 1 in which the crosslinking monomer comprises a compound of theformula III in which R⁹ is an aliphatic group.
 6. A polymer according toclaim 1 in which the monomers include a mixture of at least twocross-linking monomers of the general formula III, in at least one ofwhich R⁹ is an aromatic group and in at least one of which R⁹ is analiphatic group.
 7. A polymer according to claim 6 in which the molarratio of crosslinking monomer in which R⁹ is aromatic to crosslinkingmonomer in which R⁹ is aliphatic is in the range 10:1 to 1:10.
 8. Apolymer according to claim 1 in which the zwitterionic monomer ispresent in molar amount in the range 1 to 95% based on totalethylenically unsaturated monomer.
 9. A polymer according to claim 1 inwhich the aromatic group containing monomer is present in a molar amountin the range 10 to 99% based on total ethylenically unsaturated monomer.10. A polymer according to claim 1 in which the crosslinking monomer ispresent in a molar amount in the range 0.01 to 10% based on totalethylenically unsaturated monomer.
 11. A polymer according to claim 1 inwhich the zwitterionic group has the general formula IV

in which the moieties X⁴ and X⁵, which are the same or different, are—O—, —S—, —NH— or a valence bond and W⁺ is a group comprising anammonium, phosphonium or sulphonium cationic group and a group linkingthe anionic and cationic moieties which is a C₁₋₁₂-alkylene group.
 12. Apolymer according to claim 11 in which X is a group of formula V:

where the groups R¹⁶ are the same or different and each is hydrogen orC₁₋₄ alkyl, and m is from 1 to
 4. 13. A gel comprising a polymeraccording to claim 1 swollen by a liquid.
 14. A gel according to claim13 in which the liquid is aqueous.
 15. A refractive device formed of apolymer according to claim
 1. 16. A device according to claim 15 whichhas an average transmission for visible light in the range 400 to 700 nmwavelength of at least 90% when swollen by water.
 17. A device accordingto claim 15 which comprises an absorber of electromagnetic radiation.18. A device according to claim 15, having a refractive index when fullyswollen in water on the range 1.45-1.60.
 19. A polymerisation processfor preparing a cross linked polymer, in which a polymerisation mixturecontaining ethylenically unsaturated monomers is subjected to radicalpolymerisation, whereby addition polymerisation of the ethylenicallyunsaturated groups takes place, and in which the monomers include a) azwitterionic monomer of the general formula I YBX  I wherein B is astraight or branched alkylene, oxaalkylene or oligo-oxaalkylene chainoptionally containing one or more fluorine atoms or, if X or Y containsa terminal carbon atom bonded to B, a valence bond; X is a zwitterionicgroup; and Y is an ethylenically unsaturated polymerisable groupselected from the group consisting of

CH₂═C(R)—CH₂—O—, CH₂═C(R)—CH₂OC(O), CH₂═C(R)OC(O), CH₂═C(R)—O—,CH₂═C(R)CH₂OC(O)N(R¹)—, R²OOCCR═CRC(O)—O—, RCH═CHC(O)O,RCH—C(COOR²)CH₂—C(O)—O—,

wherein R is hydrogen or a C₁-C₄ alkyl group; R¹ is hydrogen or a C₁-C₄alkyl group or R¹ is —B—X where B and X are as defined above; and R² ishydrogen or a C₁₋₄ alkyl group or BX where B and X are as defined above;A is —O— or —NR¹—; K is selected from the group consisting of—(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR³—,—(CH₂)_(p)NR³C(O)—, —(CH₂)_(p)C(O)NR³—, —(CH₂)_(p)NR³C(O)O—,—(CH₂)_(p)OC(O)NR³—, —(CH₂)_(p)NR³C(O)NR³— (in which the groups R³ arethe same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, and optionally incombination with B, a valence bond and p is from 1 to 12 and R³ ishydrogen or a C₁-C₄ alkyl group; b) an aromatic group containing monomerof the general formula II Y¹R⁴  II wherein Y¹ is selected from the groupconsisting of

CH₂═C(R⁵)—CH₂—O—, CH₂═C(R⁵)—CH₂OC(O)—, CH₂═C(R⁵)OC(O)—, CH₂═C(R⁴)—O—,CH₂═C(R⁵)CH₂OC(O)N(R⁶)—, R⁷OOCR⁵═CR⁵C(O)—O—, R⁵CH═CHC(O)O—,R⁵CH═C(COOR⁷)CH₂—C(O)—O—,

wherein: R⁵ is hydrogen or a C₁-C₄ alkyl group; R⁶ is hydrogen or aC₁-C₄ alkyl group or R⁶ is R⁴; R⁷ is hydrogen or a C₁₋₄ alkyl group orR⁴; A¹ is —O— or —NR⁶; K¹ is selected from the group consisting of—(CH₂)_(q)OC(O)—, —(CH₂)_(q)C(O)O—, —(CH₂)_(q)OC(O)O—, —(CH₂)_(q)NR⁸—,—(CH₂)_(q)NR⁸C(O)—, —(CH₂)_(q)C(O)NR⁸—, —(CH₂)_(q)NR⁸C(O)O—,—(CH₂)_(q)OC(O)NR⁸—, —(CH₂)_(q)NR⁸C(O)NR⁸— (in which the groups R⁸ arethe same or different), —(CH₂)_(q)O—, —(CH₂)_(q)SO₃—, and a valence bondand q is from 1 to 12 and R⁸ is hydrogen or a C₁-C₄ alkyl group; and R⁴is an aromatic group; and c) a cross-linking monomer of the generalformula II (Y²)_(n)R⁹  III in which n is an integer of at least 2, eachY² is selected from the group consisting of

CH₂═C(R¹⁰)—CH₂—O—, CH₂═C(R¹⁰)—CH₂OC(O)—, CH₂═C(R¹⁰)OC(O)—, CH₂═C(R¹⁰)O—,CH₂═C(R¹⁰)CH₂OC(O)N(R¹¹)—, R¹²OOCCR¹⁰═CR¹⁰C(O)—O—, R¹⁰CH═CHC(O)O—,R¹⁰CH═C(COOR¹²)CH₂—C(O)—O—,

wherein: R¹⁰ is hydrogen or a C₁-C₄ alkyl group; R¹¹ is hydrogen or aC₁-C₄ alkyl group; R¹² is hydrogen or a C₁₋₄ alkyl group; A² is —O— or—NR¹¹—; K² is selected from the group consisting of —(CH²)_(r)OC(O)—,—(CH²)_(r)C(O)O—, —(CH₂)_(r)OC(O)O—, —(CH₂)_(r)NR¹²,—(CH₂)_(r)NR¹²C(O)—, —(CH₂)_(r)C(O)NR¹²—, —(CH₂)_(r)NR¹²C(O)O—,—(CH₂)_(r)OC(O)NR¹²—, —(CH₂)_(r)NR¹²C(O)NR¹²— (in which the groups R¹²are the same or different), —(CH₂)_(r)O—, —(CH₂)_(r)SO₃— and a valencebond and r is from 1 to 12 and R¹² is hydrogen or a C₁-C₄ alkyl group;and R⁹ is an n-functional organic group; wherein the cross-linkedpolymer is swellable in water such that the water content of the polymerwhen fully swollen in deionized water is in the range of 10 to 50% byweight, and the zwitterionic monomer of general formula I is present inthe crosslinked polymer in an amount of at least 5 mole %, the aromaticgroup containing monomer of general formula II is present in thecrosslinked polymer in an amount of at least 10 mole %, and thecross-linking monomer of general formula III is present in thecrosslinked polymer in an amount of 0.01 to 10 mole %, based upon totalmonomer.
 20. A process according to claim 19 in which the zwitterionicmonomer is present in molar amount in the range 1 to 95% based on totalethylenically unsaturated monomer.
 21. A process according to claim 19in which the aromatic group containing monomer is present in a molaramount in the range 10 to 99% based on total ethylenically unsaturatedmonomer.
 22. A process according to claim 19 in which the crosslinkingmonomer is present in a molar amount in the range 0.01 to 10% based ontotal ethylenically unsaturated monomer.
 23. A process according toclaim 19 in which polymerisation is initiated by a thermal, a redox or aU.V. initiator.
 24. A process according to claim 19 in which thezwitterionic monomer and aromatic group containing monomer areimmiscible in the absence of a co-solvent, and in which thepolymerisation mixture contains a co-solvent which is anon-polymerisable liquid whereby the polymerisation mixture is ahomogeneous solution.
 25. A process according to claim 24 in which theco-solvent is an alcohol.
 26. A process according to claim 24 in whichthe co-solvent is present in the polymerisation mixture in an amount inthe range 5 to 90% by weight.
 27. A process of forming a refractivedevice in which a polymerisation process according to claim 24 iscarried out, the co-solvent is removed from the product polymer to forma xerogel which is substantially free of co-solvent, and the xerogel isshaped by cutting to a predetermined three dimensional shape.
 28. Aprocess according to claim 27 in which the refractive device is anintraocular lens.
 29. A process of forming a refractive device in whicha polymerisation process according to claim 24 is carried out whilst thepolymerisation mixture is in a mould and, after polymerisation, thesolvent is removed from the polymer.
 30. A process according to claim 27in which after the said cutting step, the xerogel is swollen in aqueousliquid.
 31. A polymer according to claim 4 in which R⁹ is a bisphenol Agroup.
 32. A polymer according to claim 5 in which R⁹ is an ethylene oran oligo(ethyleneoxy)ethylene group.
 33. A polymer according to claim 6in which the aromatic group is a bisphenol A group and the aliphaticgroup is an ethylene or oligo(ethyleneoxy)ethylene group.
 34. A polymeraccording to claim 1 in which the zwitterionic monomer is present in amolar amount in the range 10 to 25%. The aromatic group containingmonomer is present in a molar amount in the range 75 to 90% and thecross-linking monomer is present in a molar amount in the range 0.5 to3%, each based on total ethylenically unsaturated monomer.
 35. A polymeraccording to claim 11 in which X⁴ and X⁵ are O and W⁺ is a group offormula —W¹N⁺R¹⁴ ₃, —W¹—P⁺R¹⁵ ₃, —W¹—S⁺R¹⁵ ₂ or —W¹—Het⁺ in which: W¹ isalkylene of 2-6 carbon atoms optionally containing one or moreethylenically unsaturated double or triple bonds, disubstituted-aryl,alkylene aryl, aryl alkylene, or alkylene aryl alkylene, disubstitutedcycloalkyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylenecycloalkyl alkylene, which group W¹ optionally contains one or morefluorine substituents and/or one or more functional groups; and eitherthe groups R¹⁴ are the same or different and each is hydrogen, selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms and aryl, ortwo of the groups R¹⁴ together with the nitrogen atom to which they areattached form a heterocyclic ring containing from 5 to 7 atoms or thethree groups R¹⁴ together with the nitrogen atom to which they areattached form a fused ring structure containing from 5 to 7 atoms ineach ring, and optionally one or more of the groups R¹⁴ is substitutedby a hydrophilic functional group, and the groups R¹⁵ are the same ordifferent and each is R¹⁴ or a group OR¹⁴, where R¹⁴ is as definedabove; or Het is an aromatic nitrogen-, phosphorus- orsulphur-containing ring.
 36. A polymer according to claim 12 in which mis 2 and each R¹⁶ is methyl.
 37. A process according to claim 29 inwhich the solvent is removed from the polymer after the polymer has beenremoved from the mould, and in which the polymer is subsequently swollenin an aqueous liquid.
 38. A process according to claim 19 in which themonomers include a mixture of at least two cross-linking monomers of thegeneral formula III, in at least one of which R⁹ is an aromatic groupand in at least one of which R⁹ is an aliphatic group.
 39. A processaccording to claim 38 in which the zwitterionic monomer is present in amolar amount in the range 10 to 25%, the aromatic group containingmonomer is present in a molar amount in the range 75 to 90% and thecross-linking monomer is present in a molar amount in the range 0.5 to3%, each based on total ethylenically unsaturated monomer.
 40. A processaccording to claim 19 in which the zwitterionic group has the generalformula IV

in which the moieties X⁴ and X⁵, which are the same or different, are—O—, —S—, —NH— or a valence bond and W⁺ is a group comprising anammonium, phosphonium or sulphonium cationic group and a group linkingthe anionic and cationic moieties which is a C₁₋₁₂-alkylene group.
 41. Aprocess according to claim 40 in which X is a group of formula V: